It is known that dihydropyridine-5-phosphonate derivatives (racemate) show oral anti-hypertensive action to be effective for cardiovascular diseases such as angia pectoris, cerebrovascular disease, hypertension or the like (see, for example Patent Documents 1-7).
The above-mentioned effect is owing to vasodilation mainly based on L-type calcium channel blocking action, and similar to that of L-type calcium antagonists represented by other numeral 1,4-dihydropyridine derivatives.
Recently, it was found that efonidipine (racemate) being a representative compound of dihydropyridine-5-phosphonate derivatives has T-type calcium channel blocking action in addition to L-type calcium channel blocking action (see, for example, Non-patent Document 1).
It is reported that the activation of T-type calcium channel participates in occurrence of hypercardia (see, for example Non-patent Document 2), heart failure (see, for example Non-patent Document 2), cardiomyopathy (see, for example Non-patent Document 3), tachyarrhythmia represented by atrial fibrillation (see, for example Non-patent Document 4), arterial sclerosis (see, for example Non-patent Document 5), renal disorder represented by nephritis/nephropathy (see, for example Non-patent Document 6), renal insufficiency (see, for example Non-patent Document 6), inflammation and edema (see, for example Non-patent Document 7), hyper-aldosteronism (see, for example Non-patent Document 8), neurogenic pain (see, for example Non-patent Document 9), and epilepsy (see, for example Non-patent Document 10). Therefore, it is though that T-type calcium channel blockers are effective for therapy or prevention of these diseases.    Patent Document 1: JP 61-30591 A (1986)    Patent Document 2: JP 60-69089 A (1985)    Patent Document 3: JP 1-275591 A (1989)    Patent Document 4: JP 61-63688 A (1986)    Patent Document 5: JP 63-233992 A (1988)    Patent Document 6: JP 62-169795 A (1987)    Patent Document 7: JP 62-169796 A (1987)    Non-patent Document 1: Masumiya H et al.: Eur J Pharmacol 335,p. 15-21 (1997)    Non-patent Document 2: Mulder P et al.: J Am Coll Cardiol 29, p. 416-421 (1997)    Non-patent Document 3: Villame J et al.: Cardiovasc Drugs Ther 15, p. 41-48 (2001)    Non-patent Document 4: Fareh S et al.: Circulation 100, p. 2191-2197 (1999)    Non-patent Document 5: Noll G and LuscherTF: Cardiology 89, p. 10-15 (1998)    Non-patent Document 6: Baylis C et al.: Am J Kidney Dis 38 p. 1292-1297 (2001)    Non-patent Document 7: Bilici D et al.: Pharmacol Res 44, p. 527-531 (2001)    Non-patent Document 8: Lenglet S et al.: Endocrinology 143, p. 1748-60 (2002)    Non-patent Document 9: McCallum J B et al.: Anesthesiology 98, p. 209-216 (2003)    Non-patent Document 10: Porcello D M et al.: J Neurophysiol 89, p. 177-185 (2003)
However, dihydropyridine-5-phosphonate derivatives represented by efonidipine (racemate) have a possibility that the influence thereby on vasodilation and cardiac function based on L-type calcium channel blocking action becomes hindrance factors in the therapy of the above-mentioned diseases. In addition, they are liable to cause lowering in Quality of Life, such as headache, flash, dizziness, edema or the like based on vasodilation.
From the above, it is considered very useful to find T-type calcium channel blockers having a weak or little L-type calcium channel blocking action.
The present inventors eagerly investigated in order to solve the above-mentioned problems. As a result of it, they found that optically active dihydropyridine-5-phosphonate derivatives in which the absolute configuration of 4-position on dihydropyridine ring is R-configuration show a weak or little L-type calcium channel blocking action, and a selective blocking action against T-type calcium channel, and they completed the present invention.